Whole-Exome Sequencing Reveals a Rapid Change in the Frequency of Rare Functional Variants in a Founding Population of Humans

Abstract

Whole-exome or gene targeted resequencing in hundreds to thousands of individuals has shown that the majority of genetic variants are at low frequency in human populations. Rare variants are enriched for functional mutations and are expected to explain an important fraction of the genetic etiology of human disease, therefore having a potential medical interest. In this work, we analyze the whole-exome sequences of French-Canadian individuals, a founder population with a unique demographic history that includes an original population bottleneck less than 20 generations ago, followed by a demographic explosion, and the whole exomes of French individuals sampled from France. We show that in less than 20 generations of genetic isolation from the French population, the genetic pool of French-Canadians shows reduced levels of diversity, higher homozygosity, and an excess of rare variants with low variant sharing with Europeans. Furthermore, the French-Canadian population contains a larger proportion of putatively damaging functional variants, which could partially explain the increased incidence of genetic disease in the province. Our results highlight the impact of population demography on genetic fitness and the contribution of rare variants to the human genetic variation landscape, emphasizing the need for deep cataloguing of genetic variants by resequencing worldwide human populations in order to truly assess disease risk.

When Is Selection Effective?

“…We have argued that other popular measures for the efficacy of selection (Lohmueller et al 2008;Casals et al 2013;Lohmueller 2014;Henn et al 2016) are biased in out-of-equilibrium populations studied over short time scales. Many previous claims that selection acted differentially in human populations (Lohmueller et al 2008;Casals et al 2013) could be explained by these biases.…”

“…Many previous claims that selection acted differentially in human populations (Lohmueller et al 2008;Casals et al 2013) could be explained by these biases. Confirming this interpretation, Fu et al (2014) found no differences in the average frequency of deleterious alleles between African Americans and European Americans in the ESP 6500 data set (NHLBI GO Exome Sequencing Project 2012).…”

“…The reduction in diversity has been observed in human populations that have undergone strong population bottlenecks. For example, heterozygosity decreased in populations that left Africa and further decreased with successive founder events (Tishkoff et al 1996;Ramachandran et al 2005;1000 Genomes Project Consortium 2012; Casals et al 2013). The effect of demography on the accumulation of deleterious variation has been more elusive in both humans and nonhuman species.…”

The Effect of an Extreme and Prolonged Population Bottleneck on Patterns of Deleterious Variation: Insights from the Greenlandic Inuit

“…This suggests that the GI population has likely been small and isolated for a long period of time after the OOA dispersal took place. Analyses of the GI population could therefore contribute to understanding patterns of deleterious variation and genetic load in small populations [e.g., Casals et al (2013) and Lim et al (2014)].…”

Leveraging ancestry to improve causal variant identification in exome sequencing for monogenic disorders

“…[27][28][29]51 Using simulated exome data we investigated the efficacy of filtering across a wide range of methods and sequencing studies. When comparing the methods that do not leverage ancestry, we observe that the NoAncestry, FNR o5% approach leads to a slightly increased number of variants that need to be functionally followed up over the NoAncestry, f41% approach ( Table 2).…”